PROJECT SUMMARY Ventricular tachycardia (VT), a life-threatening fast heart rhythm, occurs frequently in patients with myocardial infarction, leading to sudden cardiac death. Catheter-based ablation offers the possibility of permanent cure by interrupting the VT reentrant circuit. Unfortunately, eliminating infarct-related VT with ablation has achieved only modest success, 50-88%. This stems from limitations associated with the current VT electrical mapping and the use of the clinical VT maps to identify the target locations for ablation. Employing new strategies that provide comprehensive understanding of the complex phenomena in the zone of infarct, and how they correlate to clinical measures is a quest of paramount clinical signi?cance, as will lead to a signi?cant improvement in the identi?cation of optimal ablation targets for infarct-related VT. The overall objective of this project is to apply novel imaging and modeling methodologies to provide a comprehensive understanding of the complex micro-structural and electrophysiological (EP) factors that establish speci?c VT pathways in the zone of the healed infarct and to determine how these factors are re?ected in clinical imaging and EP measurements. Our ability to achieve this objective stems from new developments by our team, such as the invention of a new MRI pulse sequence that allows us to acquire non- destructively images of entire human and large animal hearts ex-vivo at previously unattainable (sub-millimeter) resolution. We will use our new sub-millimeter imaging capability to acquire contrast-enhanced and diffusion- tensor MRI of swine and human hearts ex-vivo and develop individualized models from these images. These high resolution ex-vivo models will be used to test a number of novel mechanistic hypotheses elucidating how the complex spatially-distributed structural and EP characteristics of the healed infarct establish preferential VT pathways through it. We will then conduct simulation and experimental research to establish the relationship between the infarct structural and EP characteristics at the sub-millimeter scale that give rise to speci?c VT pathways, and the image features and electrical signatures in corresponding clinical-resolution measurements. Successful execution of the proposed studies will provide a new understanding of the signatures of the com- plex infarct-related micro-structural and EP remodeling as they are manifested in clinical measurements. The new insight will enable improved determination of the optimal ablation option for a given VT, leading to a signi?cant advancement in the ef?cacy of the therapy.